CN103446234A - Multi-variant and multi-phase salvia miltiorrhiza solid self-microemulsion, application thereof in preparation of drug and preparation method thereof - Google Patents
Multi-variant and multi-phase salvia miltiorrhiza solid self-microemulsion, application thereof in preparation of drug and preparation method thereof Download PDFInfo
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- CN103446234A CN103446234A CN2013104233699A CN201310423369A CN103446234A CN 103446234 A CN103446234 A CN 103446234A CN 2013104233699 A CN2013104233699 A CN 2013104233699A CN 201310423369 A CN201310423369 A CN 201310423369A CN 103446234 A CN103446234 A CN 103446234A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a multi-variant and multi-phase salvia miltiorrhiza solid self-microemulsion, application thereof in preparation of a drug and a preparation method thereof. A solid self-microemulsion composition is prepared from the following components by weight: 0.1-10g of salvia miltiorrhiza multi-component extract, 10-30g of emulsifier, 5-20g of co-emulsifier, 10-30g of oil phase and 20-50g of solid adsorbent. Two components (total tanshinones and salvianolic acids) in the salvia miltiorrhiza are simultaneously loaded to one preparation; in vivo absorption of a plurality of ingredients in the salvia miltiorrhiza is improved. By adopting the preparation method, the stability of the self-microemulsion preparation can be increased; the dosage of a surfactant is greatly reduced; meanwhile, the bioavailability of a multi-component extract of the salvia miltiorrhiza is improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a multi-element multi-phase pellet solid self-microemulsion for resisting cardiovascular diseases, application thereof in preparing medicines and a preparation method thereof. Namely, the stability and the bioavailability of the multi-component salvia miltiorrhiza extract are improved by preparing the multi-component multi-phase solid self-microemulsion.
Technical Field
Salvia miltiorrhiza is a dried root and rhizome of Salvia milirrhiza Bge of Labiatae, has effects of dispelling blood stasis, relieving pain, promoting blood circulation, regulating menstruation, clearing heart fire and relieving restlessness, and is widely used for treating cardiovascular and cerebrovascular system diseases in clinic. The effective parts of Saviae Miltiorrhizae radix with blood circulation promoting and blood stasis dispelling effects mainly comprise two main groups, i.e. liposoluble diterpene ketone compounds tanshinone I, tanshinone IIA, cryptotanshinone, etc., and water soluble phenolic acid components such as salvianolic acid A, salvianolic acid B, tanshinol, protocatechualdehyde, etc. The two active ingredients have the effects of resisting platelet aggregation, resisting thrombosis, resisting oxidative damage, resisting atherosclerosis, reducing myocardial infarction area, reducing myocardial oxygen consumption, preventing and treating myocardial ischemia reperfusion injury, and the like.
However, the fat-soluble components of salvia miltiorrhiza have a flat rigid structure like feijing, are almost insoluble in water and have low bioavailability, and the water-soluble components are easily influenced by the discharge of P glycoprotein due to poor stability, so the clinical curative effect of the medicine is seriously influenced. As a novel pharmaceutical means, a micro-emulsion drug delivery system (MEDDS) can improve the bioavailability by dispersing the fat-soluble components and the water-soluble components of the salvia miltiorrhiza medicine into small molecules of 10-100nm, so that the salvia miltiorrhiza medicine can easily pass through the hydration membrane of the intestinal tract, and the modes of increasing lymphatic transport, inhibiting the discharge of P glycoprotein and the like are adopted. Some scholars prepare paclitaxel into microemulsion, most of which are in research stage at present, and many problems are not solved. For example, conventional microemulsions have poor stability, are not easily taken, and have high surfactant usage. In order to increase the stability of the medicine, improve the oral adaptability of the medicine and improve the bioavailability of the multi-component salvia miltiorrhiza extract, comprehensive research is carried out on a novel preparation of the multi-component salvia miltiorrhiza extract, namely multi-component multi-phase salvia miltiorrhiza solid self-microemulsion.
The solubility, the stability and the bioavailability of the multi-component salvia miltiorrhiza extract prepared into the multi-component multi-phase solid self-microemulsion are obviously improved. The multi-element multi-phase microemulsion has a round shape compared with a common microemulsion solution under the observation of an electron microscope due to the complementary characteristics of the emulsifiers with different HLB values and the oils with different properties, so that a system is more uniform, and has higher stability in actual measurement. Can also reduce the content of surfactant in the medicine and reduce toxic and side effects. In addition, the solid self-microemulsion has the characteristics of accurate dosage, convenient taking, simple preparation, stable property, suitability for industrial large-scale production and the like, and has wide clinical application prospect. However, due to the poor stability of the common microemulsion, the inconvenience of taking and the toxic and side effects caused by the need of a large amount of surfactant, some problems are faced in the actual preparation of the medicine, and the problems need to be solved by searching novel nontoxic auxiliary materials, preferably selecting proper proportion and using proper preparation technology.
Disclosure of Invention
The invention aims to solve the technical problem of providing a multi-element multi-phase salvia miltiorrhiza solid self-microemulsion for resisting cardiovascular diseases, application thereof in preparing medicaments and a preparation method thereof, and the invention loads two components (total tanshinone and salvianolic acids) in salvia miltiorrhiza in one preparation and improves the in vivo absorption of various components in salvia miltiorrhiza;
the invention can increase the stability of the self-microemulsion preparation, greatly reduce the dosage of the surfactant and simultaneously improve the bioavailability of the multi-component extract of the salvia miltiorrhiza.
The technical scheme of the invention is as follows
A multi-element multi-phase red sage root solid self-microemulsion is prepared from red sage root extract, emulsifier, assistant emulsifier, oil phase and solid adsorbent,
multi-component extract of salvia miltiorrhiza: 0.1 to 10g of a surfactant,
emulsifier: 10 to 30g of a water-soluble polymer,
auxiliary emulsifier: 5 to 20g of a mineral oil,
oil phase: 10 to 30g of a water-soluble polymer,
solid adsorbent: 20-50 g.
The invention recommends the following optimized weight ratios of the components:
multi-component extract of salvia miltiorrhiza: 1 to 5g of a surfactant, in an amount of 1 to 5g,
emulsifier: 15 to 25g of a mineral oil,
auxiliary emulsifier: 5 to 10g of a water-soluble polymer,
oil phase: 10 to 20g of a water-soluble polymer,
solid adsorbent: 40-60 g.
The multi-component extract of the salvia miltiorrhiza comprises effective components such as tanshinol, salvianolic acid B, dihydrotanshinone I, tanshinone I, cryptotanshinone, tanshinone IIA and the like. A
The multi-component multi-phase salvia miltiorrhiza solid self-microemulsion, wherein the oil phase is selected from the group consisting of: isopropyl myristate, glycerol linoleate, glycerol oleate or caprylic capric triglyceride. The emulsifier is selected from: polyoxyethylene hydrogenated castor oil, polyethylene glycol stearate 15, caprylic capric acid macrogol glyceride, polyethylene glycol lauric glyceride, oleic acid macrogol glyceride or polysorbate 80. The coemulsifier is selected from diethylene glycol monoethyl ether, polyethylene glycol 400 or ethanol. The solid adsorbent is selected from: mannitol, hydroxypropylmethylcellulose or dextran 80.
Because the common microemulsion in the prior art has poor stability, inconvenient taking and toxic and side effects caused by the need of a large amount of surfactant, the invention adopts a multi-element emulsifier and oil phase ratio and prepares the solid self-microemulsion by means of freeze drying and spray drying for improving the oral adaptability and stability of the medicine.
The scheme for completing the second invention task of the application is as follows: the multi-element multi-phase salvia miltiorrhiza solid self-microemulsion for resisting cardiovascular diseases and the application thereof in preparing medicaments.
The scheme for completing the third invention task of the present application is as follows: the preparation method of the multi-element multi-phase salvia miltiorrhiza solid self-microemulsion for resisting cardiovascular diseases is characterized by comprising the following steps:
preparing multi-component salvia miltiorrhiza extract microemulsion;
adding related auxiliary materials and mixing uniformly;
drying the extracting solution to obtain the solid self-microemulsion;
and fourthly, filling and sterilizing to obtain the product.
The preparation of the multi-component microemulsion in the step may be: the method comprises the steps of-a, directly extracting salvia miltiorrhiza decoction pieces by using microemulsion; adding a red sage root raw material medicine into prepared blank self-microemulsion and then dispersing the red sage root raw material medicine into water liquid;
the drying can be spray drying or freeze drying.
In the optimization scheme, after the steps of two seconds, one of the following steps can be added:
adding a forming auxiliary material of a solid adsorbent, and uniformly mixing by magnetic stirring (and then drying in the step III);
and b, adding a forming auxiliary material of the solid adsorbent, and mechanically stirring, ultrasonically dispersing or dispersing by using a high-pressure homogenizer (and then drying in the step three).
The invention loads two components (total tanshinone and salvianolic acid) in the salvia miltiorrhiza in one preparation simultaneously and improves the in vivo absorption of various components in the salvia miltiorrhiza; the invention can increase the stability of the microemulsion and greatly reduce the dosage of the surfactant, and simultaneously improve the bioavailability of the multi-component extract of the salvia miltiorrhiza.
The multi-element multi-phase salvia miltiorrhiza solid self-microemulsion prepared by the invention has the advantages that: the multielement multiphase microemulsion has a round shape and a more uniform system compared with a common microemulsion solution under the observation of an electron microscope due to the complementary characteristics of the emulsifiers with different HLB values and the oils with different properties, so that the solubility, the stability and the bioavailability of the multi-component salvia miltiorrhiza extract prepared into the multielement multiphase solid self-microemulsion are obviously improved. The content of the surfactant in the preparation can be reduced, so that the toxic and side effects are reduced. In addition, the solid self-microemulsion has the characteristics of accurate dosage, convenient taking, simple preparation, stable property, suitability for industrial large-scale production and the like, and has wide clinical application prospect.
The formulation is of the oil-in-water type. Compared with the common microemulsion, the microemulsion has higher chemical and physical stability, reduces toxic and side effects, reduces irritation, improves medication compliance, and makes up for the defects of the existing preparation.
Drawings
FIG. 1-1 and FIG. 1-2 show the results of the Malvern particle size analyzer;
FIG. 2 shows the results of transmission electron microscopy: wherein,
FIG. 2-1: an electron microscope form containing only one oil phase and one surfactant formula;
FIG. 2-2: only contains one oil phase, and is compounded with the surface active agent in the form of an electron microscope;
FIGS. 2 to 3: various oil phases, electron microscope morphology of surfactant formula;
FIGS. 3A-3D: the solid self-microemulsion preparation and the suspension are compared with the time curve of the danshensu, the salvianolic acid B, the cryptotanshinone and the tanshinone IIA in the rat body after oral administration (n = 6).
Detailed Description
The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein the embodiments are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are provided, but the scope of the present invention is not limited to the following embodiments.
Example 1: the method for preparing the multi-element multi-phase salvia miltiorrhiza solid self-microemulsion preparation comprises the following components:
the method comprises the following steps: mixing the medicines and the auxiliary materials according to the prescription amount, adding ten times of water, magnetically stirring, uniformly mixing until the mixture is clear and transparent, subpackaging, freezing at minus 40 ℃, and putting the mixture into a freeze dryer for freeze drying. Drying the obtained powder, filling, sterilizing and numbering to obtain the product.
Example 2:
the method comprises the following steps: mixing the medicines and the auxiliary materials according to the prescription amount, adding ten times of water, magnetically stirring, uniformly mixing until the mixture is clear and transparent, subpackaging, freezing at minus 40 ℃, and putting the mixture into a freeze dryer for freeze drying. Drying the obtained powder, filling, sterilizing and numbering to obtain the product.
Example 3:
the method comprises the following steps: mixing the medicines and the auxiliary materials according to the prescription amount, adding ten times of water, magnetically stirring, uniformly mixing until the mixture is clear and transparent, subpackaging, freezing at minus 40 ℃, and putting the mixture into a freeze dryer for freeze drying. Drying the obtained powder, filling, sterilizing and numbering to obtain the product.
Example 4
The method comprises the following steps: mixing the medicines and the auxiliary materials according to the prescription amount, adding water in an amount which is five times that of the medicines, magnetically stirring, uniformly mixing until the mixture is clear and transparent, and sucking the mixture into a spray dryer for spray drying. Drying the obtained powder, filling, sterilizing and numbering to obtain the product.
Example 5
The method comprises the following steps: preparing blank self-microemulsion according to a prescription, and preparing the following medicinal materials: self-microemulsion: and (5) water: 1: the ultrasonic extraction is carried out twice at a ratio of 40 for 1 hour. Filtering the extractive solution, rotary film evaporating for concentration, adding solid adsorbent, mixing, packaging, freezing at-40 deg.C, and freeze drying in a freeze dryer. Drying the obtained powder, filling, sterilizing and numbering to obtain the product.
Example 6
The method comprises the following steps: preparing blank self-microemulsion according to a prescription, and preparing the following medicinal materials: self-microemulsion: ultrasonic extraction is carried out for 1 hour twice by the ratio of water to 5:1: 40. Filtering the extractive solution, rotary film evaporating for concentration, adding solid adsorbent, spray drying in spray dryer, drying to obtain powder, bottling, sterilizing, and numbering to obtain the final product.
Example 7: and (3) performing redispersibility test on the multi-element multi-phase salvia miltiorrhiza solid self-microemulsion preparation.
The method comprises the following steps:
adding 20 times of water solution into the prepared solid self-microemulsion, magnetically stirring until the solid self-microemulsion is uniformly dispersed, and measuring the particle diameter and zeta potential by using a Malvern laser particle size analyzer, which is shown in figure 1 and figure 2.
Particle size analysis results of malvern laser particle sizer:
as can be seen from figure 1, the average particle size measured after redissolution is 50.9nm, the particle size distribution is narrow, the dispersion coefficient is good, more than 90 percent of the droplets have the particle size of 10-100 nanometers, and the requirement of a self-microemulsion drug delivery system is met
Example 8: transmission electron microscope form of multi-element multi-phase salvia miltiorrhiza solid self-microemulsion preparation
The method comprises the following steps:
the microemulsion prepared by different formulas is dripped on a copper mesh, dyed by 2 percent phosphotungstic acid solution, dried and then placed into a transmission electron microscope for observing the shape. See fig. 2.
As can be seen from FIGS. 2-1, 2-2, 2-3, the multi-component and multi-phase microemulsion has a more rounded shape and a more uniform particle size distribution than a microemulsion using only one oil phase or one surfactant. The multi-phase and multi-phase microemulsion has better self-emulsifying capacity and stability.
Example 8: in order to evaluate the in vivo absorption effect of components of the multi-component multi-phase salvia miltiorrhiza solid self-microemulsion preparation, the pharmacokinetics research of the salvia miltiorrhiza multi-component extract solid self-microemulsion preparation rat by taking salvia miltiorrhiza multi-component extract suspension as a reference preparation is carried out. The specific embodiment is as follows: dividing healthy male SD rats into two groups of 6 rats, fasting (without water) for 12h before experiment, and administering single dose of radix Salviae Miltiorrhizae solid self-microemulsion (equivalent to danshensu 36 mg/kg) via intragastric administration-1Salvianolic acid B288mg kg-1Tanshinone IIA 15.42mg.kg-1Cryptotanshinone 9.6 mg/kg-1). Collecting 0.5mL of blood from retroorbital venous plexus at 5, 15, 30, 45, 60, 90, 120, 240, 360, 480, 600, 720 and 1440min after administration, placing in prepared heparin sodium anticoagulation tube, and performing 5000 r.min-1Centrifuging for 5min, collecting supernatant, separating plasma, and freezing and storing in refrigerator at-70 deg.C. Treating the blood plasma sample according to the method of 2.2 items, measuring the contents of tanshinol, salvianolic acid B, tanshinone IIA and cryptotanshinone by UPLC-MS, fitting the time curve (shown in figures 3-A-3-D), and calculating the relative bioavailability
Bioavailability (F) refers to the relative amount and rate of absorption of a drug by the body into the systemic circulation. The method comprises the following steps of dividing into absolute bioavailability and relative bioavailability, wherein the absolute bioavailability is an intravenous injection serving as a reference standard, the relative bioavailability is a comparative study among dosage forms or among different preparations of the same dosage form, and the relative bioavailability index is adopted in the experiment to evaluate the degree of absorption of the multi-element multi-phase solid self-microemulsion preparation in vivo on index components of the salvia miltiorrhiza.
The formula:
AUCtarea under the drug time curve of the solid self-microemulsion preparation group.
DosetArea under the drug administration curve of the suspension control group.
AUCrThe administration dosage of the solid self-microemulsion preparation group.
DoserAdministration dose of suspension control group.
Calculating the relative bioavailability of tanshinol, salvianolic acid B, cryptotanshinone, tanshinone IIA, the solid self-microemulsion preparation and the suspension control group according to the pharmacokinetic statistical parameters as follows:
Fsalvianic acid A=174.1%，
FSalvianolic acid B=167.6%，
FCryptotanshinone=499.3%，
FTanshinone IIA=938.2%。
The results of the four relative bioavailability show that the multi-element multi-phase solid self-microemulsion technology obviously improves the in vivo absorption of active ingredients in the salvia miltiorrhiza medicinal material, namely the tanshinol, the salvianolic acid B, the cryptotanshinone and the tanshinone IIA, by 74.1 percent, 67.6 percent, 399 percent and 838 percent respectively.
Example 9: essentially the same as example 1, with the following modifications: the weight ratio of each component is that the salvia miltiorrhiza multi-component extract: 1g of a compound; emulsifier: 15g of the total weight of the mixture; auxiliary emulsifier: 5g of the total weight of the mixture; oil phase: 10g of a mixture; solid adsorbent: 40 g.
Example 10: essentially the same as example 1, with the following modifications: the weight ratio of each component is that the salvia miltiorrhiza multi-component extract: 5g of the total weight of the mixture; emulsifier: 25g of the total weight of the mixture; auxiliary emulsifier: 10g of a mixture; oil phase: 20g of the total weight of the mixture; solid adsorbent: 60 g.
Example 11: essentially the same as example 1, with the following modifications: the weight ratio of each component is that the salvia miltiorrhiza multi-component extract: 1g of a compound; emulsifier: 25g of the total weight of the mixture; auxiliary emulsifier: 5g of the total weight of the mixture; oil phase: 20g of the total weight of the mixture; solid adsorbent: 40 g.
Example 12: essentially the same as example 1, with the following modifications: the weight ratio of each component is that the salvia miltiorrhiza multi-component extract: 5g of the total weight of the mixture; emulsifier: 15g of the total weight of the mixture; auxiliary emulsifier: 10g of a mixture; oil phase: 10g of a mixture; solid adsorbent: 60 g.
The above description is only exemplary of the invention, and all modifications that can be derived from the disclosure of the invention are intended to fall within the scope of the invention.
Claims (10)
1. The multi-element multi-phase salvia miltiorrhiza solid self-microemulsion is characterized in that the composition consists of a salvia miltiorrhiza multi-component extract, an emulsifier, an auxiliary emulsifier, an oil phase and a solid adsorbent, wherein the weight ratio of the components is as follows:
multi-component extract of salvia miltiorrhiza: 0.1 to 10g of a surfactant,
emulsifier: 10 to 30g of a water-soluble polymer,
auxiliary emulsifier: 5 to 20g of a mineral oil,
oil phase: 10 to 30g of a water-soluble polymer,
solid adsorbent: 20-50 g.
2. The multi-element multi-phase salvia miltiorrhiza solid self-microemulsion according to claim 1, wherein the weight ratio of each component is as follows:
multi-component extract of salvia miltiorrhiza: 1 to 5g
Emulsifier: 15 to 25g
Auxiliary emulsifier: 5 to 10g
Oil phase: 10 to 20g
Solid adsorbent: 40-60 g.
3. The multi-component multi-phase red sage root solid self-microemulsion according to claim 1, wherein the multi-component extract of red sage root comprises tanshinol, salvianolic acid B, 2-hydro-tanshinone I, cryptotanshinone, tanshinone IIA.
4. The multi-component multi-phase Salvia miltiorrhiza solid self-microemulsion according to claim 1,
the oil phase is selected from: isopropyl myristate, glycerol linoleate, glycerol oleate or caprylic capric triglyceride;
the emulsifier is selected from: polyoxyethylene hydrogenated castor oil, polyethylene glycol stearate 15, caprylic capric acid macrogol glyceride, polyethylene glycol lauric glyceride, oleic acid macrogol glyceride or polysorbate 80;
the coemulsifier is selected from diethylene glycol monoethyl ether, polyethylene glycol 400 or ethanol;
the solid adsorbent is selected from: mannitol, hydroxypropylmethylcellulose or dextran 80.
5. The multi-element multi-phase salvia miltiorrhiza solid self-microemulsion according to claim 1, wherein the multi-element multi-phase salvia miltiorrhiza solid self-microemulsion is prepared by adopting the following method:
the method comprises the steps of extracting the salvia miltiorrhiza medicinal material by using the microemulsion prepared by the formula;
adding related auxiliary materials and mixing uniformly;
drying the extracting solution to obtain the solid self-microemulsion;
and fourthly, filling and sterilizing to obtain the product.
6. The use of the multi-phase multi-red sage root solid self-microemulsion for cardiovascular disease resistance of claim 1 in the preparation of a medicament.
7. The method for preparing the multi-component multi-phase salvia miltiorrhiza solid self-microemulsion for resisting the cardiovascular diseases as claimed in claim 1, which is characterized by comprising the following steps:
preparing multi-component salvia miltiorrhiza extract microemulsion;
adding related auxiliary materials and mixing uniformly;
drying the extracting solution to obtain the solid self-microemulsion;
and fourthly, filling and sterilizing to obtain the product.
8. The method for preparing the multi-component multi-phase salvia miltiorrhiza solid self-microemulsion resistant to the cardiovascular diseases according to claim 7, is characterized in that the preparation operation of the multi-component microemulsion in the step is as follows: the method comprises the steps of-a, directly extracting salvia miltiorrhiza decoction pieces by using microemulsion; the method comprises the steps of adding a multi-component salvia miltiorrhiza extract bulk drug into prepared blank self-microemulsion and then dispersing the multi-component salvia miltiorrhiza extract bulk drug into water liquid.
9. The method for preparing the multi-component multi-phase red sage root solid self-microemulsion for resisting cardiovascular diseases according to claim 7, wherein the drying in the step three is spray drying or freeze drying.
10. The method for preparing the multi-element and multi-phase salvia miltiorrhiza solid self-microemulsion for resisting the cardiovascular disease as claimed in claim 7, 8 or 9, is characterized in that one of the following steps is added after the steps:
adding a forming auxiliary material of a solid adsorbent, and uniformly mixing by magnetic stirring;
and (b) adding a forming auxiliary material of the solid adsorbent, and mechanically stirring, ultrasonically dispersing or dispersing by using a high-pressure homogenizer.
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| CN105878815A (en) * | 2016-06-24 | 2016-08-24 | 凌云 | Traditional Chinese medicinal self-microemulsion fast-release drop pill for treating coronary heart disease and preparation method |
| CN109045109A (en) * | 2018-10-23 | 2018-12-21 | 郑州大学 | A kind of chitosan-modified Salvia root P.E two-phase medicament-carried nano lipid carrier and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104644553A (en) * | 2015-02-11 | 2015-05-27 | 山西中医学院 | Tanshinone IIA micro-emulsion preparation, tanshinone IIA micro-emulsion gel preparation and preparation methods of preparations |
| CN104644553B (en) * | 2015-02-11 | 2017-10-20 | 山西中医学院 | A kind of tanshinone IIA microemulsions, tanshinone IIA microemulsion gel preparation and their preparation method |
| CN105878815A (en) * | 2016-06-24 | 2016-08-24 | 凌云 | Traditional Chinese medicinal self-microemulsion fast-release drop pill for treating coronary heart disease and preparation method |
| CN109045109A (en) * | 2018-10-23 | 2018-12-21 | 郑州大学 | A kind of chitosan-modified Salvia root P.E two-phase medicament-carried nano lipid carrier and preparation method thereof |
| TWI763071B (en) * | 2020-10-07 | 2022-05-01 | 國泰醫療財團法人國泰綜合醫院 | Microemulsion and its use, pharmaceutical composition and pharmaceutical use |
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